1. Field of the Invention
The invention provides methods and systems for the treatment of patients afflicted with coronary or peripheral artery disease. More particularly, the invention provides methods and systems for the treatment of ischemic tissue through a periodic, local administration of a vasoconstrictive drug to an open artery adjacent to regions of ischemic tissue.
2. Description of the Background
Ischemia is a condition which results from insufficient blood flow to an area of the body, usually due to an occlusion in a blood vessel. Ischemic heart disease results from insufficient coronary blood flow, which in turn is frequently caused by atherosclerosis. In certain persons who have a genetic predisposition to this condition, or in persons who eat excessive quantities of cholesterol and other fats, large quantities of cholesterol gradually become deposited beneath the intima (the innermost of three layers making up the blood vessel wall). Later, these areas of cholesterol deposit become invaded by fibrous tissue, and they also frequently become calcified. As a result, atherosclerotic plaque develops that protrudes into the vessels and either blocks or partially blocks blood flow. A very common site of development of atherosclerotic plaque is the first few centimeters of the coronary arteries, in which case the patient may suffer from myocardial ischemia.
FIG. 1 is an illustration of a mammalian heart 10. Major arteries for heart 10 include the right coronary artery (xe2x80x9cRCAxe2x80x9d) 12, the left anterior descending artery (xe2x80x9cLADxe2x80x9d) 14, and the left circumflex (xe2x80x9cLCXxe2x80x9d) 16. If an occlusion 18 were to develop at the top of LAD 14, then an ischemic region 20 (delineated by a hatch pattern) would develop within heart 10, because this region of the heart would not be receiving an adequate supply of oxygenated blood. In this case, LAD 14 may be termed an xe2x80x9coccludedxe2x80x9d vessel.
A compensatory mechanism is observed in some ischemic patients, wherein collateral vessels 22a, 22b, 22c, and 22dadjacent to ischemic region 20 enlarge so as to carry more blood from RCA 12 toward ischemic region 20. Of course, collateral vessels originating at LCX 16 could also (or alternatively) enlarge to carry more blood to ischemic region 20. This process is termed xe2x80x9carteriogenesis.xe2x80x9d
Occlusions and arteriogenesis are also seen in other areas of the body. For example, occlusions of the superficial femoral artery (xe2x80x9cSFAxe2x80x9d), which feeds blood to a person""s leg, are common. In some patients, an enlargement of collateral vessels is observed, similar to the above-mentioned example of myocardial ischemia.
The precise mechanisms responsible for such arteriogenesis have not been definitively determined. A current theory is that arteriogenesis involves the concerted action of various growth factors, including vascular endothelial growth factor (VEGF), acidic and basic fibroblastic growth factors (aFGF and bFGF, respectively), platelet-derived endothelial cell growth factor (PD-ECGF), monocyte chemotractant factor (MCP1), and transforming growth factor xcex21(TGF-xcex21). See, e.g., Simons et al., xe2x80x9cClinical Trials in Coronary Angiogenesis: Issues, Problems, Consensusxe2x80x9d Circulation, 102:e73-e86, 2000; Chilian et al., xe2x80x9cMicrovascular Occlusions Promote Coronary Collateral Growthxe2x80x9dAm. J Physiol., 248 (4pt 2): H1103-11, 1995; Kersten et al., xe2x80x9cDC Modulation of Coronary Collateral Angiogenesis: a Canine Model of Neo-vascularization Induced by Chronic Ischemia,xe2x80x9dJ Card Surg, 10:354-7, 1995; Sorman et al., xe2x80x9cEnhanced External Counterpulsation in the Management of patients with Cardiovascular Disease,xe2x80x9dClin. Cardiol., 22:173-8, 1999.
Since the precise mechanisms for arteriogenesis have not been definitively determined, currently no single method for stimulating arteriogenesis exists which offers proven, predictable, repeatable results. Methods being used in or considered for use in clinical trials include protein therapy and gene therapy.
Protein therapy involves the repeated administration of growth factor proteins to the patient. Protein therapy allows administration of precise amounts of growth factors with a well-defined half-life, pharmacokinetics, and safety record. Unfortunately, since the process of arteriogenesis is not fully understood, it is not known what growth factor protein, or combination of growth factor proteins, should be administered to the patient. Several methods may be used to administer the growth factor proteins, but each method has its drawbacks. Such methods include intravenous infusions, and for the specific case of myocardial ischemia, intracoronary infusions and intramyocardial delivery.
Intravenous infusions, while practical and low-cost, may result in undesirable side effects, such as nitric oxide-mediated hypotension, due to the high concentration of growth factor protein(s) required for systemic administration.
Intracoronary infusions are easily performed in a cardiac catheterization laboratory and are also applicable in most patients with coronary artery disease. However, the need for left heart catheterization limits this approach to a single session or, at most, infrequent repetitions. Moreover, intracoronary infusions may result in systemic exposure to the growth factor protein and may precipitate systemic hypotension. Finally, both intravenous and intracoronary infusions are associated with relatively low uptake in the target ischemic tissue. It has been observed that very small amounts of the growth factor (e.g., often less than 1%) remain in the ischemic myocardium one hour after intravenous or intracoronary administration.
Intramyocardial delivery is another method of delivering growth factor proteins, offering the advantages of targeting the desired areas of the heart, likely higher efficiency of delivery, and prolonged tissue retention. However, intramyocardial delivery is very invasive, requires highly specialized equipment, and requires a high skill level of the operator.
Theoretically, arteriogenesis could also be stimulated by the introduction of genes encoding growth factor proteins, rather than administration of the growth factor proteins themselves. An argument in favor of gene therapy is that it may facilitate sustained local production of growth factors by the patient. However, the use of gene therapy also has drawbacks. While conventional drugs work outside cell walls, the DNA encoding the growth factor(s) must penetrate not only the cell wall, but also the nucleus within the cell. The fraction of cells that actually take up and express the new DNA is quite low, typically a few percent, and at best 10-20%. Secondly, the DNA that actually enters the cell nuclei may be attacked by the patient""s immune system. When the immune system is activated in this manner, the immune system may also harm healthy genes in the target cells and other nearby cells. Thus, gene therapy in its present form is associated with much more variability in the levels of the proteins produced and duration of expression than is protein therapy.
Thus, there is a need for a mechanism for stimulating arteriogenesis that does not suffer from the disadvantages described above.
The present invention treats ischemia by causing brief periods of occlusion of blood flow in an otherwise open target vessel adjacent to the ischemic region. The periods of occlusion are caused by means of periodic administration of a therapeutically effective amount of a vasoconstrictor to the target vessel. It is anticipated that the periods of occlusion will re-route blood flow to collateral vessels, increase shear stress on these collateral vessels and cause them to release growth factor proteins. This, in turn, induces the enlargement of the collateral vessels, with the result of increased blood flow to the ischemic region. Thus, the invention contemplates stimulating the natural production of all growth factor proteins associated with arteriogenesis in a specific region of the body, rather than by the systemic or local administration of selected growth factor proteins, or local administration of DNA, as in the prior technology.
Exemplary modes of practicing the invention are discussed herein. In a first mode, delivery of a vasoconstrictor is achieved by means of an external or implanted pump system that stores and delivers the vasoconstrictor through an implanted catheter that extends between the pump and a selected portion of the target vessel. A preselected volume of the vasoconstrictor is periodically delivered from the pump to the target vessel. Each dose of the vasoconstrictor causes a brief period of occlusion of the target vessel, which induces shear stress in collateral vessels, and leads to the desired arteriogenesis. Advantageously, this mode of practicing the invention offers targeted delivery of a known quantity of the vasoconstrictor to arterioles at a specific region of the target vessel. Moreover, the vasoconstrictor can be administered multiple times to the patient over the course of weeks, with only two surgical procedures being performed if the embodiment including the implantable pump is used.
In a second mode of practicing the invention, a layer of polymer is deposited on the luminal surface of the target vessel. Microspheres that are adapted to attach to the layer of polymer are periodically injected into the patient""s body. The microspheres contain a selected amount of the vasoconstrictor. Sufficient time is allowed for the microspheres to attach to the layer of polymer, where the microspheres subsequently release the vasoconstrictor. The vasoconstrictor causes a brief period of occlusion of the target vessel, which induces the above-mentioned shear stress in collateral vessels. As with the first mode, it is anticipated that the collateral vessels will enlarge over time due to the shear stress induced by occlusion of the target vessel, thereby developing increased blood flow to the ischemic region. Advantageously, the second mode of practicing the invention likewise offers targeted delivery of a known quantity of the vasoconstrictor to arterioles at a specific region of the target vessel. Moreover, the vasoconstrictor, being contained within a microsphere which is chemically bound to the wall of the target vessel, is not likely to be washed out from the vessel by diffusion and convection within the vessel into surrounding tissues.
Vasoconstrictors that may be used in accordance with the present invention, include, but are not limited to, epinephrine, norepinephrine, lysine vasopressin, 8-arginine vasopressin, angiotensin II, and methoxamine hydrochloride, and analogs of these compounds.
These and other aspects of the present invention may be better understood through the drawings and the following detailed description of the exemplary embodiments.